5&#39;,6&#39;-dihydro-2h-pyran-4&#39;-yl ethers of progestational steroids



United States Patent m 3,513,164 5' ,6 -DIHYDRO-2H-PYRAN-4 -YL ETHERS OF PROGESTATIONAL STEROIDS Alexander D. Cross, Mexico City, Mexico, and John A.

Edwards, Los Altos, Califl, assignors to Syntex Corporation, Panama, Panama, a corporation of Panama N0 Drawing. Continuation-impart of application Ser. No. 731,267, May 22, 1968. This application Oct. 9, 1968, Ser. No. 766,328

Int. Cl. C07c 173/00 US. Cl. 260239.55 44 Claims ABSTRACT OF THE DISCLOSURE The 5',6'-dihydro-2H-pyran-4'-yl ethers of progestational steroids have high oral activities.

This is a continuation-in-part of application Ser. No. 731,267 filed May 22, 1968.

This invention relates to novel and useful 5',6'-dihydro- 2H-pyran-4'-yl ethers of progestational steroids, the steroid nucleus thus bearing a new group represented by the formula In the preferred embodiment, this new group is added at the C-3 position of pregnane progestational agents and at the C-3, (3-176, or C3,17 fi positions of the androstane progestational agents.

The preferred progestational steroidal ethers of this invention can be represented by the formulas:

wherein R is hydrogen or methyl; R is lower alkyl or lower cycloalkyl; R is methyl or ethyl; R is lower alkenyl, such as vinyl and propenyl, lower alkynyl (including lower haloalkynyl with a halogen, such as fluoro,

3,513,164 Patented May 19, 1970 chloro, or bromo), such as ethynyl, fluoroethynyl, chloroethynyl, propynyl, trifiuoropropynyl, and the like, and

Rm R20 wherein R and R each is hydrogen, chloro, or fluoro; R R and R each is hydrogen, methyl, fiuoro, or chloro; in Formula II when Z is a double bond, R is absent; in Formula V when Z is a single bond, R can have either an a or ,8 orientation; R and R each is hydrogen or, taken together, a methylene group having the formula aa L 'JJJ RaB wherein R and R each is hydrogen, chloro, or fluoro; R is keto or .H wherein R is hydrogen, chloro, or hydroxyl; and when R is hydrogen, R and R is hydrogen; R is hydrogen, chloro, or fiuoro; R is methylene,

wherein R and R each is hydrogen or methyl, or taken together with R is wherein R and R each is hydrogen, alkyl, or aryl, the latter two groups having up to eight carbons; R is hydrogen, hydroxyl, or conventional hydrolyzable esters thereof; R is hydrogen or fluoro; X is 5,6'-dihydro-2H- pyran-4'-yloxy; X is keto,

wherein R is X, hydrogen, hydroxy, or conventional hydrolyzable esters thereof; X is X, hydroxy, or conventional hydrolyzable esters thereof; and at least one of X and X in Formulas II, III, and IV is X; Z, and Z each is a single bond or double bond; and Z is a single bond, double bond, or a single bond in combination with a methylene group having the formula wherein R and R each is hydrogen, chloro, or fiuoro.

The term progestational steroid is used herein to denote those steroids having progestational activity. The preferred progestational steroids have 5',6-dihydro-2H-pyran-4'-yl ether groups at positions C-3, C-17/i, or C3,17{3 of the steroid nucleus.

The compounds represented by Formulas I-V, inclusive, are progestational agents useful in the treatment of menstrual disorders and fertility control and can be used in the same manner as 17a-acetoxy6-chloropregna-4,6- diene 3,20- dione (chloromadinone acetate). The 16- methylene species are particularly useful in estrus synchronization in domestic animals. These compounds are administered by the usual routes, whether orally or parenterally, either alone or in conjunction with other medicinal agents, or in pharmaceutically acceptable, non-toxic compositions formed by the incorporation of any of the normally employed excipients.

The term (lower)alkyl and derivations thereof appearing in the above definitions and elsewhere in the instant specification denote alkyl groups containing from one to six carbon atoms, inclusive, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, amyl, hexyl, and the like.

The term conventional hydrolyzable ester as used herein denotes those hydrolyzable ester groups conventionally employed in the steroid art, preferably those derived from hydrocarbon carboxylic acids or phosphoric acids and their salts. The term hydrocarbon carboxylic acid defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic), can be of straight chain, branched chain, or cyclic structure, and preferably contain from one to 12 carbon atoms. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to six carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like, attached to the hydrocarbon backbone chain. Typical conventional hydrolyzable esters thus included within the scope of the term and the instant invention are acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate, diethylacetate, trimethylacetate, t-butylacetate, trimethylhexanoate, methylneopentylacetate, cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi-fl,[3-dimethylglutarate, acetoxyacetate, 2 chloro 4 nitro benzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, B- chloropropionate, trichloroacetate, B-chlorobutyrate, dihydrogen phosphate, dibenzyl phosphate, benzyl hydrogen phosphate, sodium benzyl phosphate, cyclohexylammonium benzyl phosphate, sodium phenyl phosphate, sodium ethyl phosphate, di-p-nitrobenzyl phosphate, sodium o-methoxyphenyl phosphate, cyclohexylammonium p-cyanobenzyl phosphate, sodium phenacyl phosphate, benzyl o-carbomethoxyphenyl phosphate, and the like.

The term aryl is included aryl, aralkyl, and alkaryl groups, such as phenyl, p-chlorophenyl, p-methoxyphenyl, benzyl, phenethyl, tolyl, ethylphenyl, and the like. The wavy line (2) designates and includes both the alpha and beta configurations.

The novel 175-(5',6'-dihydro-2H-pyran-4-yloxy) ethers of Formula I and 3/8-(S',6-dihydro-2l-I-pyran-4-yloxy) ethers of Formula V can be prepared from the corresponding respective 17B-hydroxy and 3;3-hydroxy compounds as shown by the following:

4 wherein 13 16, 17 18, 21, R36: 37 40 42 43 R R X and Z have the meanings indicated above with respect to Formulas I and V.

In carrying out the above illustrated process, the 175- hydroxy compounds of Formula I are reacted under substantially anhydrous conditions with an excess of 4'- (lower)alkoxy-S,6'-dihydro-2H-pyran; for example, with from about two to about 50 or more molecular equivalents for each hydroxyl group in the steroid starting material, in the presence of a small amount of an acidic catalyst, such as hydrochloric acid, p-toluenesulfonic acid, boron trifluoride etherate, and the like, either alone or together with an inert, organic solvent, such as benzene, diethyl ether, methylene chloride, or the like, at a temperature ranging from about 0 C. to about 80 C. (preferably at around room temperature, i.e., 25 C.) for about five minutes to about 48 hours, thus giving the corresponding l-(5',6'-dihydro-2H-pyran-4-yloxy) ethers represented by Formula I.

The 36 (5,6-dihydro-2H-pyran-4'-yloxy) ethers of Formula V are prepared by reacting the Bil-hydroxy compounds of Formula V under anhydrous conditions with 4' (lower) alkoxy-5',6-dihydro-2H-pyran in the presence of an inorganic solvent, such as benzene, diethyl ether, methylene chloride and the like, and in the presence of a catalytic amount of a stable sulfonyl chloride, such as p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, p-nitrobenzenesulfonyl chloride, and the like, at temperatures of from 0 C. to C. (preferably at room temperature) for from five minutes to 48 hours.

In carrying out these reactions, a second series of ethers corresponding to those represented by Formulas I-V, inclusive, but wherein X is a 4'-(lower)alkoxytetrahydro-4'-yloxy group are also formed. Use of hydrocarbon solvents for the reaction medium, higher catalyst concentrations, and longer reaction times increase the yield of the 5,6'-dihydro-2H-pyran-4'-yloxy compounds.

The starting materials represented by Formula I are known in the art or are obtainable by known methods from known steroids. See, for example, US. Pat. No. 3,067,214.

The starting materials represented by Formula V' are known in the art or are obtainable from known steroids by known methods. See, for example, US. Pat. No. 3,365,446. The Formula V steroids are obtained from the 3-keto precursor steroids by reduction of the 3'-keto group such as with lithium tri-t-butoxy aluminum hydride, lithium trimethoxy aluminum hydride, and the like in an inert, organic solvent, such as tetrahydrofuran, ether, monoglyme, and the like, at a temperature of from room temperature for rapidly reduced compounds up to reflux conditions for compounds exhibiting lower rates of reduction.

The 3-keto precursor steroids for the above elaboration are prepared by processes described in US. Pat. 3,338,928 and Ser. No. 499,092, filed Oct. 20, 1965. One particularly useful and novel class of precursors are the 1,2 methylene-6,7-difiuorornethylene-17u-acyloxypregn- 4-en-3-ones and the corresponding 17a-hydr0xy and 17adeshydroxy derivatives thereof, the preparation of which is described in detail hereinafter.

The methyleneation reaction hereof by which a halomethylene group is added in at least one of positions C-1,2 and C-6,7 involves treatment of a conjugated unsaturated steroid with a molar excess of an alkali or alkaline earth metal salt of a haloacetic acid, such as bromodichloroacetic acid, trichloroacetic acid, dichlorofluoroacetic acid, difluorochloroacetic acid, and the like.

It is preferable to conduct this reaction after certain labile substituents, such as hydroxy groups, have been protected. This protection is preferably accomplished by converting them to esters, tetrahydropyranyl ethers, or ketones which groups readily facilitate the regeneration of the hydroxyl. This preference is not an absolute necessity, however, for while free hydroxy groups will often become involved in side reactions under the conditions of the process, they can be readily regenerated by execution of a mild hydrolysis after completion of the reaction.

The fused methylene group is introduced by reaction of the unsaturated steroid with dimethylsulfoxonium methylide base in dimethylsulfoxide. Alternatively, reductive dehalogenation of the halomethylene group, inserted via the methyleneation reaction described above, such as with lithium aluminum hydride affords the fused methylene group in lieu thereof.

The conjugated unsaturated starting steroid may be prepared in a number of ways. For example, in the introduction of a double bond between carbons 1 and 2, the A ring of the 3-keto -2O-ethylenedioxy-A compound is first reduced with lithium metal in liquid ammonia pro viding the 3-keto-5a-pregnane (allopregnane). Upon treatment of the allopregnane thus obtained with bro mine, sodium acetate, and p-toluenesulfonic acid, the 2- bIOInO-3-k6tO-5owPI6gI1flHC is obtained which is dehydro brominated with calcium carbonate in dimethylacetamide to afford the A -unsaturated derivative. Thereafter, the corresponding 1,2-halomethylene derivative or, alternatively, the 1,2-methylene derivative is prepared as de* scribed hereinbefore. The introduction of a double bond between carbons 4 and 5 results from a sequence of bromination followed by dehydrobromination as described above. The A -diene system is provided by treating the 1,2-substituted-3-keto-4-ene with chloranil in the presence of ethylacetate and acetic acid. The 20-ethylenedioxy protecting group is removed with p-toluenesulfonic acid in ethanol at room temperature, yielding the 20-keto group. Thus, for example, the 1,2-methylenepregn-4-en- 3-ones and 1,2methylenepregna-4,6--dien-3-ones of this invention are prepared as well as the 1,2-halomethylene derivatives thereof.

To provide a 6,7-halomethylene or -methylene substituent, a 3-keto-4,6-diene system is first generated, such as by treating the corresponding 3-keto-4'-ene with chloranil in the presence of ethylacetate and acetic acid, as described above, followed by introduction of the C-6,7 substituent as described above thus giving the 3-keto-4- ene containing a 6,7-halomethylene or -methylene group, i.e., the 6,7-halomethylenepregn-4-en-3-ones and 6,7- methylenepregn-4-en-3-ones.

The halomethylene or methylene group may similarly be inserted at position C-6,7 in a 1,2-substituted-3-keto- 4,6-diene which is provided via the procedure outlined above. Thus obtained are the 1,2;6,7-bis(halomethylene)- pregn-4-en-3-ones and the corresponding methylene derivatives thereof.

The addition of the methylene and halomethylene groups in accordance with the procedures set forth herein at either of positions C1,2 and O-6,7 is accomplished with the orientation of the resultant fused grouping including both isomeric alpha and betaconfigurations in variable ratios. The isomeric product mixture in each instance is conveniently and readily subjected to conventional techniques, such as chromatography, fractional crystallization, and the like, by which the alpha and beta isomers are separated by virtue of their different physical properties. Each isomer can thereafter be subjected to further elaboration at other parts of the molecule.

In some instances, one particular configurational isomer predominates in the reaction mixture. Thus, for example, Cl,2 additions of either the methylene or halomethylene group usually favor the alpha isomer. The presence of an llfl-hydroxyl orients the C-6,7 methylene predominantly to the beta configuration, but does not alter the usual alpha to beta ratio in the halomethylene series. Beta addition in the halomethylene series is favored by the presence of a 9a-halo substituent.

The substituents represented by R and R are preferably present in the starting steroids of Formula V a1- though the 6-halo groups may be introduced by converting the 3-keto-4-ene to its enol ether, such as by treatment with ethyl orthoformate and treating the thus prepared enol ether intermediate with N-chlorosuccinimide or perchloryl fluoride, respectively, yielding a 3-keto-4,6- diene containing a 6-chloro or 6-fluoro group.

The enol ether may also be treated with N-bromo-succinimide and the resultant 6-bromo compound then dehydrobrominated with calcium oxide to yield the 3-keto-4,6- diene. This upon treatment with chromyl chloride yields the 6,7-chlor0hydrin which, when subjected to the action of hydrogen bromide in acetic acid, affords the 3-keto-6- chloro-4,6-diene.

The substituents represented and defined by R and R may be present in the starting steroid or they may be subsequently introduced via conventional procedures. Thus, an llfi-hydroxy compound is dehydrated to yield the 9(1 1 )-ene. This compound is converted to the 96,11B- oxido through the bromohydrin intermediate. Treatment of the oxido compound with hydrogen fluoride or hydrogen chloride then yields the 9u-fluoro-1lB-hydroxy or 9u-chloro-11/3-hydroxy compounds. Alternatively, the 9(l1)-ene is treated with chlorine to yield the 9a,l1/3-dichloro derivative.

The substituents represented by R and R are present in the starting steroid. l6a,l7o-acetals and -ketals are prepared through treatment of a 16u,17a-dihydroxy compound with an aldehyde or ketone in the presence of an acid, such as perchloric acid. The resultant acetal or ketal, for example, a l6a,l7a-isopropylidenedioxy derivative may be utilized as a final compound or as an intermediate, the group being cleaved with regeneration of the diol by the action of hydrofluoric acid.

The 16methylene group is present in the starting steroid and can be introduced as disclosed in U.S. Pat. 3,262,950 from a l6-methylpregna-4,l6-diene-3,20-dione or l6-methyl-l9-norpregna-4, l 6-diene-3,20-dione. The Cl6,17 double bond is selectively epoxidized with hydrogen peroxide, for example, in a lower alkanol or other solvent, to form the l6a,l7a-oxido group which is then cleaved to form the 16-methylene-l7whydroxy or -acetoxy derivative in a solvent of a mineral acid or acetic anhydride, respectively, in a solvent of low ionizing power, such as benzene.

The substituents represented by R are present in the starting steroid and can be introduced as described in U.S. Pat. 3,262,950. For example, the ZI-unsubstituted compound can be reacted with iodine in the presence of calcium oxide and methanol in tetrahydrofuran to form the 2l-iodo intermediate which is then reacted with silver fluoride, for example, to form the 21-fluoro derivative.

The 4'-(lower)alkoxy-S,6-dihydro-2H-pyran reactants used to form the ethers of this invention can be prepared by well-known methods. For example, tetrahydro-4-pyrone can be reacted with a primary or secondary lower alkanol under acidic conditions to form the intermediate, 4',4-di(lower)alkoxytetrahydropyran, which upon distillation with an acid, such as toluenesulfonic acid or mesitylenesulfonic acid, yields the 4-(lower) alkoxy-5',6'- dihydro-ZH-pyran product. Such a method is described by Reese et al., J. Am. Chem. Soc, 89, 3367 (1967). The lower alkanol is preferably methanol but it can be other lower alcohols, such as ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, amyl alcohol, hexanol, and the like, to form the corresponding pyrans, such as, for example, 4'-methoxy-5',6-dihydro-2H-pyran, 4'-et'hoxy- 5,6'-dihydro-2H-pyran, etc.

The 3-, 17,8-, and 3,l7fl-bis(5',6'-dihydro-2H-pyran-4- yloxy) ethers represented by Formulas II, III, and IV can be prepared from the corresponding androsten-17/3-o1-3- one and l9-norandrosten-l7 6-ol-3-one compounds by a process which can be illustrated schematically as follows for the compounds of Formula 11.

In these formulas, R R R R R Z and X have the meanings given with respect to Formulas I-V above, and R is an alkyl, alkenyl, cycloalkenyl, or cycloalkyl group having up to 12 carbon atoms.

In carrying out the above-illustrated process, 17u-ethynylandrost-4-en-17/3-ol-3-one, for example (VI: R and R =methyl; R =ethynyl; and R and R =hydrogen) is reacted under substantially anhydrous conditions with an excess of 4-(lower)alkoxy-S,6'-dihydro-2H-pyran as described above with respect to Formula I to give the corresponding 17cc ethynyl-17B-(5',6-dihydro-2H-pyran- 4'-yloxy)androst-4-en-3-one (VII). This compound can be converted to the Bfi-hydroxy derivative by dissolving it Cit in an inert solvent such as a (lower)alkanol, such as methanol, an ether, such as dioxane or tetrahydrofuran or the like, and reacting it under neutral conditions with a metal hydride, such as lithium aluminum hydride, sodium borohydride, and the like, at temperatures ranging from room temperature to reflux temperature for from about one hour to about 24 hours, thus giving the corresponding l7a-ethyny l- (5,6'-dihydro-2H-pyran-4- yloxy)androst-4-en-3,B-ol (VIII). To obtain the Zap-ester of Formula IX, the product can be reacted with an organic acid anhydride in pyridine or with a solution of ethylmagnesium bromide and the desired organic chloride in anhydrous ether; for example, reaction with acetic anhydride yields 3B-acetoxy-l7a-ethynyl-l7fi-(5',6-dihydro-2H-pyran-4-yloxy)androst4-ene (IX: R =methyl). By this procedure, the compounds represented by Formulas VII-IX, inclusive, are obtained with other androst- 4-en-17B-ol-3-ones wherein R is hydrogen or methyl; R is ethyl or methyl; R is lower alkenyl, lower alkynyl, lower haloalkynyl, and

C:CI-I R5 Rzu wherein R and R each is hydrogen, chloro, or fluoro; and R and R each is hydrogen, methyl, fluoro, or chloro.

In carrying out the above-illustrated process to form the 3fl-(5,6-dihydro-2H-pyran-4-yloxy) ethers of Formulas XI and XII from the compounds represented by Formula VI, the keto group at C-3 is first reduced to 3fl-hydroxy such as by reaction with lithium tri-t-butoxy aluminum hydride or lithium aluminum hydride as described above with respect to Formula VIII to yield, for example, 17a-ethynylandrost-4-ene-3/3,17,8-diol. The product is then esterified with one molar equivalent of acetic anhydride by procedures described with respect to Formula IX to form a mixture of mono-esters. The 17;?3- acetoxy compounds are separated from the mixture by conventional chromatographic techniques. For example, l7a-ethylnylandrost-4-en-17B-ol-3-one (VI: R and R17 IHlhy1; R =ethynyl; and R and R :hydrogen) is reduced to l6a-ethynylandrost-4-ene-3/3,17B-diol and the product is esterified to form 17a-ethylnyl-l7fl-acetoxyandrost-4-en-3/3-ol (X). This compound is then reacted with 4-(lower)alkoxy-5,6'-dihydro-2H-pyran as described above with respect to Formula VII to yield the corresponding 3B-ether, for example, 3fl-(5,6-dihydro- 2H-py'ran-4-yloxy) 17a ethynyl-17/8-acetoxyandrost-4- ene (XI). If the 17fi-hydroxy compound as described in Formula XII is desired, the latter product is hydrolyzed by conventional procedures, for example, in a solution of potassium hydroxide in methanol, to yield the desired product, for example 35- (5',6'-dihydro-2H-pyran-4'- yloxy)-l7u-ethynylandrost-4-en-175-01. By this procedure, other 3B (5,6-dihydro-2H-pyran-4'-yloxy) compounds represented by Formulas XI and XII can be prepared from the corresponding compounds of Formula VI wherein R is hydrogen or methyl; R is methyl or ethyl; R is lower alkenyl, lower alkynyl, lower haloalkynyl, and

-C=CH C R4 \R20 wherein R and R each is hydrogen, chloro, or fiuoro; and R and R each is hydrogen, methyl, fiuoro, or chloro.

In the above-illustrated process to make the 3,8, 175- bis(5,6-dihydro-2H-pyran-4'-yloxy) ethers represented by Formula XIII, the corresponding 17/3-hydroxy-3-keto of Formula VI is first reduced by reaction with a metal hydride, such as lithium tri-t-(butoxy aluminum hydride or lithium aluminum hydride, to yield the corresponding 3fl-hydroxy compound as described above with respect to the compounds of Formula VIII. The 3,8, 17B-dihydroxy compound, for example, l7a-ethynylandrost-4-ene-3p,17B- diol, is then reacted with a molar excess of 4-(lower)- alkoxy-5',6'-dihydro-2H-pyran as described above with respect to Formula VII to yield the corresponding 3,8,

9 17/3-bis-(5,6-dihydro-2H-pyran-4-yloxy) ether, such as, for example, 3,8,17/3-bis(5',6-dihydro-2H-pyran-4-yloxy)- 17u-ethynylandrost-4-ene. By this procedure, other compounds represented by Formula XIII, wherein R R R R 1, R and X are as defined above, can be obtained from the corresponding substituted compounds represented by Formula VI.

By the above-illustrated procedures, the 35-, 176-, and 3,17fl-bis(5',6'-dihydro-2H-pyran-4'-y1oxy) 19 norandrost-S ()-enes and -19-norandrosta-4,9(10)-dienes represented by Formulas III and IV, respectively, can be prepared from the corresponding 19-norandrost-5(10)-en- 175-01-3-ones and 19-norandrosta-4,9(10)-dien-17/3-ol-3- ones.

In preparing the ethers of Formula II, and the substituents R R 18, R21, and R are present in the known starting compounds. See, for example, IACS, 80, 4717 (1958); IACS, 83, 4663 (1961);]. Pharm. Pharmacol, 9, 929 (1957); Ber., 71, 1024 (1938); Endocrinology, 65, 265 (1959); and US. Pats. 3,028,401, 3.047,592, 3,052,693, and 3,067,214.

In preparing the ethers of Formula III, the substituents R and CECR25 are also present in the known starting compounds. See, for example, JACS, 83, 4663 (1961) and Endocrinology, 65, 265 (1959).

In preparing the ethers of Formula IV, the substituents R and R are also present in the known starting compound. See, for example, IACS, 83, 4663 (1961), J. Chem. Soc., 4472 (1964), and US. Pats. 3,086,027, 3,248,294, 3,250,793, and 3,257,278.

Starting materials having an 18-methyl group (R ethyl) are obtainable by methods described by Smith et al. in Experimentia, vol. 19, pp. 394-396 (1963).

The invention is further illustrated by the following specific but non-limiting examples.

EXAMPLE 1 To a solution of 1 g. of 3-methoxy-17a-ethynylandrosta 3,5-dien-17fi-ol and 25 cc. of benzene, there are added 2 cc. of 4-methoxy-5',6-dihydro-2H-pyran. Next, approximately 5 cc. of the mixture of benzene and dihydropyran are distilled 01f to remove moisture, and the remaining mixture is then cooled to room temperature. To the cooled mixture is then added 0.1 g. of p-toluenesulfonic acid, and the resulting reaction mixture is held at room temperature for 72 hours. Following this reaction period, the reaction mixture is washed with an aqueous 5% sodium carbonate solution and then with water until a neutral pH is obtained, then dried over anhydrous sodium sulfate and evaporated to dryness. The dry residue is then chromatographed by passing it, dissolved in hexane, through a column of neutral alumina, thus giving 3 methoxy 17cc ethynyl 17B (5',6 dihydro- 2H-pyran-4'-yloxy)-androsta-3,5-diene.

EXAMPLE 2 Repeating the procedure of Example 1 but replacing 3-methoxy-17ot-ethynyllandrosta-,3,5-dien-17,8-01 with 3-methoxy- 170t-CthYI1Y1-1 8-methylandrosta-3,5-

dien-17B-o1, 3-propoxy-17vr-ethynylandrosta-3,S-dien-175-01, 3-cyclopropoxy- 17u-ethynylandrosta-3,5-dien- 17 8-01, 3-ethoxy-17a-ethynylandrosta-3,S-dien-173-01, 3-cyclopentoxy-17a-ethynylandrosta-3,S-dien-17,8-01, 3-cyclobutoxy-l7a-ethynylandrosta-3,S-dien-1713-01, 3-methoxy-17a-methylethynylandrosta-3,5-dien-175-01, 3-methoxy-17a-fluoroethynylandrosta-3,5-dien-1713-01, 3-methoxy-17a-chloroethynylandrosta-3,5-dien-17fl-ol, B-methoxy-17ot-ethyny1-19-norandrosta-3,5-dien-17fl-ol, 3-cyclopentoxy-17a-ethynyl-19'-norandrosta-3,5-

dien- 17,8-01, 3-cyclopentoxy-17a-ethynyl18-methyl-l9-norandrosta- 3,5 -dien-17 5-01, 3-methoxy-17u-ethyny1-l8-methy1-19-norandrosta- 3,5 -dien-1 7,6-01,

1 O 3-ethoxyl 7a-ethynyll8-methyl-19-norandrosta- 3,5 -dien- 1 -01, 3-methoxy- 1 70L-VlI1y1- 18-methyl- 19-norandrosta- 3,5 -dien-1 76-01, and 3 -methoxy-17ot(2",2-difluorocyclopropenyl) -18- methyl-19-norandrosta-3 ,5 -dien-1 7,8-01,

the following products are obtained:

3-methoxyl7a-ethynyl-17B- 5',6-dihydro-2H-pyran- 4'-yloxy) -18-methylandrosta-3,S-diene, 3-propoxy-17or-ethynyl-l7fl-(5 ',6-dihydro-2H-pyran- 4-yloxy androsta-3 ,5 -diene, 3-cyclopropoxy-17a-ethynyl-17fl-(5',6'-dihydro-2H- pyran-4-yloxy androsta-3,5-diene, 3-ethoxy-17a-ethynyl-17[i-(5,6-dihydro-2H-pyran- 4-y1oxy)androsta-3,5-diene, 3-cyclopentoxy-17a-ethynyl-17,B-(5',6'-dihydro-2H- pyran-4-yloxy androsta-3,5-diene, 3-cyclobutoxy-17a-ethynyl-17B- (5 ',6-dihydro-2H- pyran-4-yloxy) androsta-3 ,5 -diene, 3-methoxyl7a-methylethynyl- 17,8- 5 6'-dihydro-2H pyran-4'-yloxy androsta-3 ,5 -diene, 3-methoxy-l7a-fluoroethynyl-17,8-(5',6'-dihydro-2H- pyran-4-yloxy) androsta-3,5-diene, 3 -methoxy- 1 7a-chloroethynyl- 17,8- 5 ',6'-dihydro-2H- pyran-4'-yloxy) androsta-3 ,5 -diene, 3-methoxy-17u-ethynyl-17B-(5',6-dihydro-2H-pyran- 4'-yloxy)-19-norandrosta-3,5-diene, 3-cyclopentoxy-17a-ethynyl-17p-(5',6-dihydro-2I-I- pyran-4'-yloxy) 19-norandrosta-3,5-diene, 3-cyclopentoxy-17a-ethynyl-17fi-(5,6'-dihydro-2H- pyran-4-yloxy)-18-methyl-19-norandrosta3,5-diene, 3-methoxy-l7ot-ethynyl-17fi-(5 ,6-dihydro-2H-pyran- 4-yloxy) -18-methyl-19-norandrosta-3,5-diene, 3-ethoxy- 17u-ethynyl-17B-( 5 ,6'-dihydro-2H-pyran- 4-yloxy)-18-methyl-19-norandrosta3,5-diene, 3-methoxyc-V11'1Y1- 1713-(5 6-dihydro-2H-pyran- 4-yl0xy)-1S-methyl-19-norandrosta-3 ,S-diene, and 3-rnethoxy-17a(2",2"-difluorocyclopropenyl)-17;8- (5 ',6'-dihydro-2H-pyran-4'-yloxy) 18-methyl-19- norandrosta-3,5-diene.

EXAMPLE 3 Two milliliters of 4'-methoxy-5,6'-dihydro-2H-pyran are added to a solution of 1 g. of pregn-4-en-3B-ol-20-one in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for four days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 3l3-(5',6'-dihydr0-2H-pyran-4-yloxy)pregn-4-en 20 one which is recrystallized from pentane.

EXAMPLE 4 Repeating the procedure of Example 3 but replacing pregn-4-en-3fl-ol-20-one with 6-chloro-17a-acetoxypregna-4,6-dien-3 B-ol-20-one,

6-chloro-17ot-acetoxy-19-norpregna-4,6-dien-3fi-ol- 20-one,

6-methyl- 17a-acetoxypregna-4,6-dien-3 B-01-20-one,

6-n1ethyl-17a-acetoxy-19-norpregna-4,6-dien-3p-ol- 20-one,

6-chl0ro-16-methylene-17a-acetoxypregna-4,6-dien- 3 5-ol-20-one,

6et-chloro-16-methylene-l7ot-acetoxypregn-4-en-35-01- 3 5-ol-20-one,

Got-chloro-16-methylene-17or-acetoypregn-4-en-3fl-ol- 20-one,

6p-chloro-1 6-methylene- 1 7a-acetoxypregn-4-en-313-01- 20-one,

1 1 6a-methyl-16-methylene-17ot-acetoxypregn-4-en-3fi-ol- 20-one, GB-methyl-16-methylene-17a-acetoxypregn-4-en-3fl-ol- 20-one, 16a, 1 7a-isopropylidenedioxypregn-4-en-3 8-01-20-one, 6a-fluoro-1'6a-methylprcgn-4-en-3fi-ol-20-one, 6/8-fluoro-16a-methylpregn-4-en-3B-ol-20-one, 6u-fluoro-16B-methylpregn-4-en-3fl-ol-20-one, 6 fl-fluorol 6fi-methylpregn-4-en-3 fi-ol-ZO-one, 16cc, 17a-methylphenylmethylenedioxypregn-4-en38-01- 20-one, 6,8-fluoro-6a,7a-difiuoromethylene-17a-acetoxypregn-4- en-3 8-o1-20-one, 6a-fiuor0-17a-acetoxypregn-4-en-3,8-01-20-one, 6,9a,l lfi-trichloro- 17a-acetoxypregna-4,-6+iien-3 8-01- 20-one, 6-chloro-9u-fluoro-17a-acetoxypregna-4,6-dien-3[3, 1

diol--one, 6-chl0r0-17a-capr0yl0xypregna-4,6-dien-3[3-0l-20-one, 6a-methylpregn-4-en-318-01-11,20-dione, 901,1 1fl-dichloropregn-4-en-3l3-ol-20-one, 9a-fluoropregn-4-en-3 5,1 lp-diol-ZO-one, 6-methylpregna-4,6-dien-3 [3-01-1 1,20-dione, 6-methyl- 17oc-acet0Xypregna-4,6-dien-3 8-01-1 1,20-dione, 6a,16a-dimethylpregn-4-en-3fl-ol-ZO-one, and pregn-4-en-3 13-01- 1 1 13,20-dione,

the following products are obtained:

3 p- 5 ',6'-dihydro-2H-pyran-4'-y1oxy) -9a,1 1 fi-dichloropregn-4-en-3 [3-01-20-one,

3 B- 5 ,6'-dihydro-2H-pyran-4-yloxy -6-methylpregna- 4,6-dien-3 {3-01- 1 1,20-di0ne,

3 p3- 5 ,6-dihydro-2H-pyran-4'-yloxy) -6-methyl- 17aacetoXypregna-4,6-dien-3B-ol-11,20-dione,

3 5- 5',6'-dihydro-ZH-pyran-4-yloxy) -6a, l6a-dimethylpregn-4-en-20-one, and

3 e- 5 ,6'-dihydro-2H-pyran-4'-yloxy) pregn-4-en-1 1,20-

dione.

EXAMPLE 5 Repeating the procedure of Example 3 with other pregn-4-en-3fl-ol-20-ones and 19-norpregn-4-en-3B-ol-20- ones having at position C-6, hydrogen, methyl, fluoro, and chloro groups (both a and ,8 oriented when the C-6,7 bond is a single bond); at position C-Qu, hydrogen, chloro, or fluoro (hydrogen for 19-nor compounds); at position C-11, keto or in the ,B-orientation-hydrogen, chloro, and hydroxy (hydrogen for 19-nor compounds); at C16, methylene, hydrogen, tit-methyl, p-methyl; at Cc,17oc, methylenedioxy, isopropylidenedioxy, ethylphenylmethylenedioxy; at C17a, hydrogen, hydroxy, and acetoxy; at C-21, hydrogen or fluoro; at each of C1 ..2 and C6,7, a single bond, double bond, or methylene, methylmethylene, dimethylmethylene, dichloromethylene, chloromethylene, difiuoromethylene, and fluoromethylene group-the corresponding 35-(5',6-dihydro-2H-pyran-4'- yloxy)pregn-4-en-20-ones are obtained e.g.,

EXAMPLE 6 Repeating the procedure of Example 1 but replacing 3- methoxy-17a-ethynylandrosta-3,5-dien-17fl-ol with ethynyl 19 norandrost-4-en-17fi-ol-3-one-17a-ethynyl- 17B-(5',6'-dihydro 2H pyran-4'-y1oxy)-19-norandrost-4- en-3-one is obtained.

Similarly, repeating this procedure with other 19-norandrost 4-en-l7 3-ol-3-ones, androst-4-e'n-17,8-o1-3-ones, 19-norandr0sta-4,6-dien-17}30l-3-ones, and androsta-4,6- dien-17 3-o1-3-0nes having hydrogen, methyl, chloro, or fluoro groups at the C-6a and/or C-6fl position (or at the C-6 position for the 4,6-dienes); hydrogen or methyl at C-l8; and ethynyl, vinyl, methylethynyl, chloroethynyl, fiuoroe'thynyl, or 2",2-difluorocycl0propenyl groups at C-17a yields the corresponding 17;3-(5',6-dihydro-2H- pyran-4'-yloxy) compounds, e.g.,

EXAMPLE 7 A solution of 1 g. of 17a-ethynyl17fl-(5,6-dihydro- 2H-pyran-4-yloxy)-19-norandrost-4-en-3-one in 50 ml. of tetrahydrofuran is added over a 30-minute period to a stirred suspension of 1 g. of lithium tri-t-butoxy aluminum hydride in 50 ml. of anhydrous tetrahydrofuran and this mixture is heated at reflux for two hours. To the mixture are cautiously added 5 ml. of ethylacetate and 2 ml. of water. Sodium sulfate is next added, the mixture is filtered, and the solid thus collected is washed with hot ethylacetate. The combined organic solutions are then evaporated to yield l7a-ethynyl-l7fi-(5',6-dihydro-ZH- pyran-4-yloxy)-19-norandrost-4-en-3B-0l which may be further purified through recrystallization from acetone: hexane.

Similarly, repeating this procedure with other products of Example 6 yields the corresponding 3,8-hydroxy derivatives, e.g.,

A mixture of 1 g. of 17a-ethynyl-17fi-(5',6-dihydro- 2H uyran 4'-y1oxy)-19-norandrost-4-en-3fl-ol, 4 ml. of pyridine, and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water, and dried to yield 35 acetoxy 17tx-ethynyl17fi-(5,6'-dihydro-2H-pyran- 4-yloxy)-19-norandrost-4-ene which may be further purified through recrystallization from acetone:hexane.

Similarly, repeating this procedure with other products of Example 7 yields the corresponding 3 ,B-acetoxy derivatives, e. g., 3B-acetoxy-17a-ethyny1- 176- (5 ',6'-dihydro-2H- pyran 4'-yloxy)-18-methyl-19-norandrost-4-ene, 3,8-acetoxy a ethynyl (5',6 dihydro-2H-pyran-4- yloxy)androst 4-ene, 3fi-acetoxy-17a-ethyny1-17fi-(5',6- dihydro 2Hpyran-4-yloxy)-18-methylandrost-4-ene, and the like.

EXAMPLE 9 Repeating the procedure of Example 7 but replacing 17oz ethynyl 175 (5',6'-dihydr0-2H-pyran-4-yloxy)- 19-norandrost-4-en-3-one with 17a-ethynyl-19-norandrost 4 en 17B ol3-one-17ot-ethynyl-19-norandrost-4-ene- 3fl,17;8-diol is obtained.

A mixture of 1 g. of Not-ethynyl-19-norandrost-4-ene 35,17,8-diol, 4 ml. of pyridine, and 2 ml. of acetic am hydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water, and the solid which forms is collected by filtration, washed with 1 Water, and dried. The mixture is chromatographed on neutral alumina, eluting with etherzhexane, to yield 170;- ethynyl-17 3-acetoxy-19-norandrost-4en-3;3-ol.

Repeating this sequence of procedures with other 19- norandrost 4 en 17f3-ol-3-ones, androst-4-en-17fl-ol-3- ones, 19-norandrosta-4,6-dien-17fi-0l-3-ones, and androsta- 4,6-dien-17fl-ol-3-ones having hydrogen, methyl, chloro, or fluoro groups at C-6a and/or C-6fi (at C-6 with 4,6- dienes); ethynyl, methylethynyl, chloroethynyl, or fluoro ethynyl groups at C17a; and hydrogen or methyl groups at C-18 yields the corresponding 3fl-hydroxy-l7a-ester compounds, e.g.,

17oz ethynyl -17p acetoxy-lS-mcthyl-19-norandrost-4- 170a methylethynyl 17B acetoxy-I9-norandrost-4-en- 17a chloroethynyl 17 3 acetoxy-19-norandrost-4-en- 170:. fluoroethynyl 17 3 acetoxy-19-norandrost-4-en- 60; methyl 17oz ethynyl-17,8-acetoxy-19-norandrost-4- en-Bfi-ol,

60c chloro 17a ethynyl-17,6-acetoxy-19-norandrost-4- en-3,B-ol,

60c fiuoro 17a ethynyl-17,8-acetoxy-19-norandrost-4- en-Bfl-ol,

65 methyl 17a ethynyl-17p-acetoxy-19-norandrost-4- en-Bfi-ol,

6,3 chloro 17oz, ethynyl-17fl-acetoxy-19-norandrost-4- en-3fi-ol,

6B fluoro 17a -ethynyl-17/8-acetoxy-l9-norandr0st-4- en-3p-ol,

601,6 3 difluoro 17a-ethynyl-17fi-acetoxy-19-norandrost- 4-ene-3fl-ol,

17a-ethynyl-17fl-acetoxyandrost-4-en-3 3-ol,

17a-ethyny1-17B-acetoxy-l8-methylandrost-4-en-3B-ol,

17a-viny1-17B-acetoxy-18-methylandrost-4-en-3;3-ol, and

17a vinyl 17 3 acetoxy-l8-methyl-19-norandrost-4,6-

dien-3p-o1.

EXAMPLE Repeating the procedure of Example 1 but replacing 3 methoxy 17a ethynylandrosta-3,5-dien-17/3-ol with 170: ethynyl 17B acetoxy-19-norandrost-4-en-3fi-ol- 3B (5',6' dihydro-2H-pyran-4'-yloxy)-17u-etl1ynyl-17flacetoxy-19-norandrost-4-ene is obtained. Similarly, substituting the other products of Example 9 in this procedure, the corresponding 3/3-ethers are obtained, e.g.,

1 6 3 3-(5,6'-dihydroxy2H-pyran-4'xyloxy)-17a-vinyl-17flacetoxyl 8-methyl-19-norandnosta-4, 6-diene, and 3 18- 5 ',6'-dihydro-2H-pyran-4'-yloxy -1 7a-ethynyl- 17B-acetoxy-18-methylandrost-4-ene.

EXAMPLE 11 A solution of 1 g. of 3/3-(5',6'-dihydro-2H-pyran-4- yloxy)-17m ethynyl-17B acetoxy-19-norandrost-4-ene in 50 ml. of methanol is heated at reflux for three hours with a solution of potassium hydroxide in 1 ml. of water. The reaction mixture is then poured into ice water and the solid which forms is collected by filtration, Washed with water to neutrality, and dried to yield 3fl-(5',6'-dihyd'ro- 2H pyran 4' yloxy)-l7u-ethynyl-19-norandrost-4-en- -01 which is recrystallized from methylene chloride: ether.

Similarly, the other 17,8-ester products of Example 10 are converted to the corresponding 17B-ols by this procedure.

EXAMPLE 12 Repeating the procedure of Example 7 but replacing 17a ethynyl 17,8 (5',6-dihydro-2H-pyran-4-yloxy)- 19-norandrost 4- en 3 one with l7a-ethynyl-l9-norandrost-4-en-17,6-ol-3-one-1h-ethynyl 19 norandrost- 4-en-3 3,l7fi-diol is obtained. Then repeating the procedure of Example 1 but replacing 3 methoxy-17a-ethynylandrosta 3,5 dien-17B-ol with 17a ethynyl-19-norandrost 4 -en-3/8,17/3-diol and using 4 ml. instead of 2 ml. of 4 methoxy 5',6'-dihydro-2H-pyran3[3,-17pbis(5,6'-dihydro 2H pyran-4'-yloxy)-l7a-ethynyl-19- norandrost-4ene is obtained.

Repeating this sequence of procedures with other 19- norandrost-4-en-17B-ol-3-ones, androst-4en-17fi-ol-3-ones, 19-norandrosta-4,6-dien-l7,6-o1-3-ones, and androsta-4,6- dien-17fl-ol-3-ones having hydrogen, methyl, chloro, or fluoro groups at C-6a and'/ or C6fl positions (at 0-6 with 4, 6-dienes); lower alkenyl, 2",2" difluorocyclopropenyl, ethynyl, methylethynyl, chloroethynyl, or fluoroethynyl groups at C-17oz; and hydrogen or methyl at C-18 yields the corresponding 3 3,17B-biethers, e.g., 3fl,17fl-bis(5',6'-dihydro 2H pyran 4'-yloxy)-17a-ethynylandrost-4rene, 3p,17B-bis(5',6'-dihydro-2H-pyran-4'-y1oxy) 17a-ethynyl-18-methyl-l9-norandrost-4-ene, and the like.

EXAMPLE 13 Repeating the procedure of Example 1 but replacing B-methoxy -17a ethynylandrosta 3,5-dien-17fi-ol with 17a ethynyl-19-norandrost-5(10)-en-17/3-o1-3-one-17aethynyl 17,3 (5',6'-dihydro-2H-pyran-4'-yloxy)-19-norandrost-5 10)-en-3-one is obtained.

Similarly, repeating this procedure with other 19-norandrost 5(10) en-l7B-ol-3-0nes having hydrogen or methyl at C-18 and vinyl, 2",2" difluorocyclopropenyl, ethynyl, methylethynyl, chloroethynyl, or fluoroethynyl groups at 0-170; yields the corresponding l7B-(5,6-dihydro-2H-pyran-4'-yloxy) compounds, e.g.,

17a-ethynyl-17B-(5',6-dihydro-2H-pyran-4-yloxy)- 18-methy1-19-norandrost-S 10) -en-3-one, 17a-methylethynyl-17,8-(5',6-dihydro-2H-pyran-4'- yloxy)-19-norandrost-5(10)-en-3-one, 17u-chloroethynyl- 17 B- 5 ,6'-dihydro-2H-pyran-4- yloxy)-19-norandrost-5 10) -en-3 -one, 17a-fiuoroethyny1-17fl-( 5'6'-dihydro-2H-pyran-4'- yloxy)-l9-norandrost-5(10)-en-3-one, 17u-methylethynyl-17B-(5,6'-dihydro-2H-pyran-4'- yloxy)-18-methyl-19-norandrost-5 10) -en-3 one, 17a-chloroethynyl-17/3-(56'-dihydro-2H-pyran-4- yloxy)-l8-methyl-19-norandrost-5(10)-en-3-one, and 17 a-fluoroethynyl-l 7 p- 5 ',6'-dihydro-2H-pyran-4'- yloxy) -l 8-methyl-9-norandrost-5 10) -en-3-one.

EXAMPLE 14 A solution of 1 g. of l7a-ethynyl-17fl-(5',6'-dihydro- 2H-pyran-4'-yloxy)-19-norandrost-5(10) -en-3 one in 50 ml. of tetrahydrofuran is added over a 30-minute period to a stirred suspension of 1 g. of lithium aluminum hydride in 50 ml. of anhydrous tetrahydrofuran and this mixture is heated at reflux for tWo hours. To the mixture are cautiously added ml. of ethylacetate and 2 ml. of water. Sodium sulfate is next added, the mixture is filtered, and the solid thus collected is washed with hot ethylacetate. The combined organic solutions are then evaporated to yield 17a ethynyl 17/3-(56'-dihydro-2H-pyran-4'- yloxy)-19-norandrost-5(10)-en-3fl-ol which may be further purified through recrystallization from acetone: hexane.

Similarly, repeating this procedure with other products of Example 13 yields the corresponding 3B-hydroxy derivatives, e.g.,

17a-ethynyl-17fi- (5,6-dihydro-2H-pyran-4'-yloxy) 18-methyl-19-norandrost-5 -en-3B-ol, 17u-methylethynyl17B-(5,6-dihydro-2H-pyran-4'- yloxy) -19-n0randrost-5(-10) -en-3,B-ol, 17a-chloroethynyl-17B- (5',6'-dihydro-2H-pyran-4- yloxy 1 9-norandrost-5 10 -en-3,8-ol, 17u-fluoroethynyl- 17 5 6-dihydro-2H-pyran-4- yloxy) 19-norandrost-5 10 -en-3fi-ol, l7a-methylethynyl-17B- (5,6'-dihydro-2H-pyran-4'- yloxy)-1S-methyl-19-norandrost-5 10) -en-3 ,6-01, 17u-chloroethynyl-17,3-(5,6-dihydro-2H-pyran-4- yloxy)-18-methyl-19-norandrost-5( 10 -e11-3fi3-01, and 17a-fiuoroethynyl-17B- 5 ,6'-dihydro-2H-pyran-4- yloxy)-18-methyl-19-norandrost-5 10 -en-3 [9-01.

EXAMPLE 15 A mixture of 1 g. of 17u-ethyny1-17,8-(5,6-dihydro-4- yloxy)-l9-norandrost-5(10)-en-3B-ol, 4 ml. of pyridine, and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, Washed with water, and dried to yield 3,8-acetoxy- 17a-ethynyl-17fl (5',6-dihydro-2H-pyran-4'-yloxy)-19- norandrost 5(10)-ene Which may be further purified through recrystallization from acetonezhexane.

Similarly, repeating this procedure with other products of Example 4 yields the corresponding 3 3-acetoxy derivatives, e.g., Sfi-acetoxy-lh-ethynyl-17B(5,6-dihydro-2H- pyran-4-yloxy)-18-methyl-19-norandrost 5(10) ene, 3fi-acetoxy-17a-ethynyl-17,8-(5,6-dihydro 2H pyran- 4'-yloxy) androst-5 (10)-ene, 3/3-acetoxy-17a-ethynyl-17fi- (5, 6'-dihydro-2H-pyran-4'-yloxy) 18 methylandrost- 5(10)-ene, and the like.

EXAMPLE 16 Repeating the procedure of Example 14 but replacing 17a-ethynyl-17B-(5',6'-dihydro-2H-pyran 4 yloxy)-19- norandrost-5(10)-en-3-one with 17a-ethynyl 19 norandrost 5 (10) en-17(3-ol-3-one17a-ethynyl-19-norandrost-5 (10)-ene-3/3,17/3-diol is obtained.

A mixture of 1 g. of Net-ethynyl-19-norandrost-5(10)- ene-3B,17fi-diol, 4 ml. of pyridine, and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water, and the solid which forms is collected by filtration, washed with water, and dried. The mixture is chromatographed on neutral alumina, eluting With etherzhexane, to yield 17methynyl- 17 ,B-acetoxy- 1 9-norandrost-5 10) -en-3 fi-ol.

Repeating this sequence of procedures with other 19- norandrost-S(10)-en-l7,B-ol-3-ones having vinyl, 2",2"- difluorocyclopropenyl, ethynyl, methylethynyl, chloroethynyl, or fiuoroethynyl groups at 0-17 and hydrogen or methyl groups at C-18 yields the corresponding 3,8 hydroxy-17a-ester compounds, e.g.,

17a ethynyl 17B acetoxy-18-methyl-l9-norandrost- 5(10)-en-35-o1,

17a methylethynyl 17p acetoxy-19-norandrost-5(10)- en-Sfl-ol,

17a chloroethynyl 17B acetoxy-l9-norandrost-5(10)- en-3fi-ol,

17a fiuoroethynyl 17,8 acetoxy-19-norandrost-5-(10)- en-3B-ol,

17oz methylethynyl 17p acetoxy-lS-methyl-19-n0randrost-5 10) -en-3',B-ol,

17a chloroethynyl 17;? acetoxy-18-methy1-19-norandrost-5 l 0) -en-3,8-ol, and

: fluoroethynyl 17,8 acetoxy-18-methyl-19-norandrost-5 10)-en-313-ol.

EXAMPLE l7 Repeating the procedure of Example 1 but replacing 3-methoxy-l7a-ethynylandrosta-Ii,S-dien-1713-01 with 17: ethylyl 1713-acetoxy-19-norandrost-5 (10)-en-3B-ol3fi- (5,6'-dihydro-2H-pyran-4'-yloxy) 17a ethynyl 17/3- acetoxy-l9-norandrost-5(10)-ene is obtained. Similarly using the other products of Example 16, the corresponding 3fl-ethers are obtained, e.g.,

3/3 (5',6'-dihydro-2H-pyran-4-yloxy) 17a-ethynyl-17B- acetoxy-18-methyl-19-norandrost-5 10)-ene,

3/? (5,6'-dihydro2H-pyran-4-yloxy) 17a methylethynyll7fi-acetoxy- 1 9-norandrost-5 (10)-ene,

3/3 (5',6-dihydro-2H-pyran-4'-yloxy) 17a chloroethynyll7p1-acetoxy-l9-norandrost-5 10) -ene,

3f (5,6-dihydro-2H-pyran-4'-yloxy) 17a methylethynyl-17,8-acetoxy-l9-norandrost-S 10)-ene.

ethynyl-l7li-acetoxy-19-norandrost-5(10)-cue, and

3,8 (5',6-dihydro-2H-pyran-4'-yloxy) 17a fluoroethynyll7,8-acetoxy-19-norandrost-5 10)-ene.

EXAMPLE 18 A solution of 1 g. of 3 8-(5',6'-dihydro-2H-pyran-4'- yloxy) 17a ethynyl-17fi-acetoxy-19-norandrost-5(10)- ene in 50 ml. of methanol is heated at reflux for three hours with a solution of potassium hydroxide in 1 ml. of water. The reaction mixture is then poured into ice water and the solid which forms is collected by filtration, washed with Water to neutrality, and dried to yield 3,8- (5',6'-dihydro-2H-pyran-4'-yloxy) l7u-ethynyl-19-norandrost-5(10')-en-17B-ol which is recrystallized from methylene chloride: ether.

Similarly, the other 17,8-ester products of Example 17 are converted to the corresponding 17,8-ols by this procedure.

EXAMPLE 19 Repeating the procedure of Example 14 but replacing 17a ethynyl-1713-(5',6'-dihydro-2H-pyran-4-yloxy)-19- norandrost 5(10) en-3-one with 17a-ethynyl-19-norandrost 5(10) en 17B-ol-3-one17u-ethynyl-19-norandrost-5(10)-ene-3;6, 17,8-diol is obtained. Then repeating the procedure of Example 1 but replacing 3-methoxy- 17cc ethynylandrost-3,5-dien--01 with 17a-ethynyl-19- norandrost-5(l0)-ene-3/3, l7fi-diol and using 4 ml. rather than 2 ml. of 4'-methoxy-5',6-dihydro-2H-pyran-3/3, 17B bis(5',6'-dihydro-2H-pyran-4-yloxy) 17a-ethynyl- 19-norandrost-5(10)-ene is obtained.

Repeating this sequence of procedures with other 19- norandrost-5(10)-en-l7B-ol-3-ones having vinyl, 2",2"- difluorocyclopropenyl, ethynyl, methylethynyl, chloroethynyl, or fluoroethynyl groups at C-l7u and hydrogen or methyl at C-l8 yields the corresponding 3f 17B-bisethers, e.g., 3,6, 17,6 bis(5',6'-dihydro-2H-pyran-4'-yloxy)- 1'7a-methylethynyl-18-methyl-9-norandrost-4-ene, 3B, 1718- bis(5',6-dihydro-2H-pyran-4'-yloxy) 17a ethynyl-18- methyl-l9-norandrost-5 (10)-ene, and the like.

EXAMPLE 20 Repeating the procedure of Example 1 but replacing 3 methoxy 17a-ethynylandrost-3,S-dien-1713-01 with 1704 ethynyl 19 norandrosta-4,9(10)-dien-17fl-ol-3- one-17a ethynyl 17 3 (,6'-dihydro-2H-pyran-4'- yloxy)-19-norandrosta-4,9(10) -dien-3-one is obtained.

Similarly, repeating this procedure with other 19-n0randrosta-4,9()-dien-17fl-ol-3-ones and 19-norandrosta- 4,9(10), 11-trien-175-ol-3-ones having hydrogen or methyl at C-18 and lower alkenyl, lower alkynyl, lower haloalkynyl, cyclopropenyl, monoand dihaloeyclopropenyl groups at C-17ayields the corresponding 17fi-(5',6'-di1- 11ydro-2H-pyran-4-yloxy) compounds, e.g.,

17a ethynyl 17,3 (5 ',6'-dihydro-2H-pyran-4'-yloxy 18-methyl-l9-norandrosta-4,9( 1O -dien-3-one,

17a fiuoroethynyl 17 f3 (5 ,6-dihydro-2H-pyran-4- yloxy) -19-norandrosta-4,9 10 -dien-3-one,

17a-fluoroethynyl-17fi- (5',6-dihydro-2H-pyran-4'- yloxy)-18-methyl-19-norandrosta-4,9(10)-dien-3-one,

17a-vinyl-17 3-(5,6-dihydro-2H-pyran-4-yloxy) -19- norandrosta-4,9( 10) -dien-3-one,

17a-vinyl-17fl-(5',6,-dihydro-2H-pyran-4'-yloxy) -18- methyl- 19-norandrosta-4,9( 10 -dien-3-one,

17a(2",2-difiuorocyclopropenyl) -17B-(5',6'-dihydro- 2H-pyran-4-y1oxy) 1 9-norandrosta-4,9( 10 -dien- 3-0ne,

1711- 2",2"-difiuorocyclopropenyl) -17;8- 5',6'-dihydro- 2H-pyran-4'-yloxy)-18-methy1-19-norandrosta-4,9 10) 1 1-trien-3-one,

17a- 2",2"-difiuorocyclopropenyl) -17/8- 5,6'-dihydro- 2H-pyran-4'-yloxy) -19-norandrosta-4,9 10) ,1 l-trien- 3-one,

17u-vinyl- 17 fl-( 5 ,6-dihydro-2H-pyran-4-yloxy) 1 8- methy1-19-norandrosta-4,9 10) ,1 1-trien-3-one,

l7u-vinyl-17B-(5,6-dihydro-2H-pyran-4-yloxy) -19- norandrosta-4,9 10),11-trien-3-one,

17ot-ethynyl-17fl-(5,6-dihydro-2H-pyran-4-yloxy)- 18- methyl-19-norandrosta-4,9(10),11-trien-3-one,

17a-ethynyl-175- 5,6-dihydro-2H-pyran-4-yloxy l 9- norandrosta-4,9 10 ,1 1-trien-3-one,

17a-fluoroethynyl-17B- 5 ,6-dihydro-2H-pyran-4'-yloxy) 18-methyl-19-norandrosta-4,9( 10),11-trien-3-one,

17a-fluoroethynyl-17fl- (5 ,6'-dihydro-2H-pyran-4'-yloxy) 19-norandrosta-4,9 10),11-trien-3-one,

17a-chloroethynyl-17B-(5',6-dihydro-2H-pyran-4'-yloxy)- 19-norandrosta-4,9( 10) -dien-3 -one, and the like.

EXAMPLE 21 A solution of 1 g. of 17a-cthynyl-17 3-(5,6'-dihydro- 2H-pyran-4-yloxy)-19-norandrosta-4,9(10)-dien 3 one in 50 ml. of tetrahydrofuran is added over a 30-minute period to a stirred suspension of 1 g. of lithium tri-tbutoxy aluminum hydride in 50 ml. of anhydrous tetrahydrofuran and this mixture is heated at reflux for two hours. To the mixture are cautiously added 5 m1. of ethylacetate and 2 ml. of water. Sodium sulfate is next added, the mixture is filtered, and the solid thus collected is Washed with hot ethylacetate. The combined organic solutions are then evaporated to yield 17a-ethynyl-17fl- (5,6'-dihydro-2H-pyran-4'-yloxy) -19- norandrosta 4,9 (10)-dien-3fl-ol which may be further purified through recrystallization from acetonezhexane.

Similarly, repeating this procedure with other products of Example yields the corresponding 3/i-hydroxy derivatives, e.g.,

17a-ethynyl-175-(5',6'-dihydro-2H-pyran-4-yloxy)-18- methyl-19-norandrosta-4,9( 10) -dien-3 3-01,

17a-fiuoroethyny1-17fl-(5,6-dihydro-2H-pyran-4'- yloxy)-19-norandrosta-4,9 10) -dien-3 13-01,

17a-fluoroethynyl-17,3-(5',6-dihydro-2H-pyran-4'-yloxy) 18-methyl-19-norandrosta-4,9( 10 -dien-3p-ol,

l7a-vinyl-1 7B- 5,6-dihydro-2H-pyran-4-yloxy) 19- norandrosta-4,9 10 -dien-3B-ol,

17 a-vinyl-17 p- 5 ',6'-dihydro-2H-pyran-4'-yloxy) -1 8- methyl-19-norandrosta-4,9( 10) -dien-3 13-01,

17 oz- ('2",2"-difiuorocyclopenyl) 17 8- (5 ',6-dihydro- 2H-pyran-4-y1oxy) -19-norandrosta-4,9 10 -dien- 319-01,

20 17a-(2.",2"-difluorocyclopropenyl) 1719-(5',6'-dihydro- 2H-pyran-4-yloxy)-1S-methyl-19-norandrosta-4,9( 10) 11-trien-3fi-ol, 17a- 2",2"-difiuorocyclopropenyl) 17 9- 5 ',6-dihydro- 2H-pyran-4'-yloxy)-19-norandrosta-4,9(10),11-trien- 313-01, 17a-vinyl-17B-(5',6-dihydro-2H-pyran-4'-yloxy)-18- methyl-19-norandrosta-4,9 10) ,1 l-trien-3 3-01, 17a-vinyl-17 3-(5,6'-dihydro-2H-pyran-4-yloxy) -19- norandrosta-4,9( 10 ,1 1-trien-3 18-01, l7a-ethynyl-17;?)-(5,6-dihydro-2H-pyran-4'-yloxy) -1 8- methyl-19-norandrosta-4,9(l0),1l-trien-3/3-ol, 17u-ethynyl-17B-(5,6-dihydro-2H-pyran-4-yloxy)- l9- norandrosta-4,9 10) ,1 1-trien-3 fi-ol, 17x-fiuoroethynyl-17fl-(5',6-dihydro-ZH-pyran-4-yloxy)- 18-methyl-19-norandrosta-4,9 10 ,1 1-trien-3 B-ol, 17a-fluoroethynyl-17,8-(5',6'-dihydro-2H-pyran-4-yloxy) 19-norandrosta-4,9( 10) ,1 1-trien-3fl-ol, 17a-fluoroethynyl-17,B-(5',6'-dihydr0-2H-pyran-4'-yloxy) 19-norandrosta-4,9(10)-dien-3fi-ol, and the like.

EXAMPLE 22 A mixture of 1 g. of 17a-ethynyl-17fi-(5',6'-dihydro- 2H-pyran-4'-yloxy)-19-norandrosta 4,9(10)-dien 35-01, 4 ml. of pyridine, and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water, and dried to yield 313 acetoxy-17a-ethynyl-l7B-(5,6-dihydro-2H- pyran-4-yloxy) -l9-norandrosta-4,9( 10) -diene which may be further purified through recrystallization from acetone: hexane.

Similarly, repeating this procedure with other products of Example 21 yields the corresponding 3B-acetoxy derivatives, e.g., 3,8 acetoxy 17u-ethynyl-17f3-(5,6'-dihydroxy-2H-pyran-4'-yloxy)-18-methyl 19 norandrosta- 4,9(10)-diene, 3/3-acetoxy-17a-ethyny1-17,8-(5',6'-dihydro- 2H-pyran-4'-yloxy)androsta-4,9(10)-diene, 3B acetoxy- 17u-ethynyl-17fl-(5',6'-dihydro-2H-pyran-4' yloxy) 18- methylandrosta-4,9(10)-diene, and the like.

EXAMPLE 23 Repeating the procedure of Example 21 but replacing 17a-ethynyl-17/3-(5',6'-dihydro 2H pyran 4-yloxy)- l9-norandrosta 4 en 3-one with l7a-ethynyl-19-norandrosta-4,9(10)-dien 1713 ol 3 one17a-ethynyl- 19-norandrosta-4,9(10)-dien-3/3,17B-diol is obtained.

A mixture of 1 g. of 17a-ethynyl-19-norandrosta-4,9 (10)-diene-35,17fl-diol, 4 ml. of pyridine, and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water, and the solid which forms is collected by filtration, washed with water, and dried. The mixture is chromatographed on neutral alumina, eluting with etherzhexane, to yield 17a-ethyny1-17fl-acetoxy-19-norandrosta-4,9( 10)- dien-3 3-ol.

Repeating this sequence of procedures with other 19.- norandrosta-4,5(10)-dien-17/8-ol-3 ones and 19-norandrosta-4,5(10),11-trien-17B-ol-3-ones having lower alkenyl, lower alkynyl, lower haloal'kynyl, cyclopropenyl, and halocyclopropenyl groups at C-17a and hydrogen or methyl groups at 0-18 yields the corresponding 3(3- hydroxy-17a-ester compounds, e.g., 17u-ethynyl-17fi-acetoxy-18-methyl-19-norandrosta- 4,9(10)-dien-3fl-ol, 17a-vinyl-17,8-acetoxy-19-norandrosta-4,9(10)-dien- 35-01, 17a-vinyl-17B-acetoxy-18-methyl-19-norandrosta- 4,9(10)-dien-3;8-ol, fluoroethynyl-17,8-acetoxy-19-n0randrosta-4,9(10)- dien-3B-ol, fiuoroethynyl-l7B-acetoxy-18-methyl-19-norandrosta- 4,9(10)-dien-3fi-ol, 17 a- (2",2"-difluorocyclopropenyl 17fl-acetoxy- 19-norandrosta-4,9(10)-dien-3/3-ol,

21 17a-(2",2"-difiuorocyclopropenyl) -17,8-acetoxy 1 8- methyl-19-norandrosta-4,9(10)-dien-3,8-ol, 17a-ethynyl-17,8-acetoxy-18-methyl-19-norandrosta- 4,9 10 -trien-3 p-ol, 17a-ethynyl-17,8-acetoxy-19-norandrosta-4,9 10 ,1 l-

trien-3 fi-ol, 17a-vinyl-17/3-acetoxy-18-methyl-19-norandrosta- 4,9 10) l 1-trien-3fl-ol, 17m-vinyl-17B-acetoxy-19-norandrosta-4,9(10),11-

trien-SB-ol, and the like.

EXAMPLE 24 Repeating the procedure of Example 1 but replacing 3- rnethoxy-l7ot-ethynylandrosta-3,S-dien 17B 01 with 170:-

ethynyl-17fl-acetoxy-19-norandrosta 4,9(10) dien 3 {3 ol3,8-(',6-dihydro-2H-pyran-4-yloxy) 17oz ethynyl- 17B-acetoxy 19 norandrosta 4,9()-diene is obtained. Similarly, substituting the other products of Example 23 in this procedure, the corresponding 3,8-ethers are obtained, e.g.,

EXAMPLE 25 A solution of 1 g. of 3,6-(5',6-dihydro-2H-pyran-4- yloxy)-17o ethynyl 17B acetoxy 19 norandrosta-4, 9(lO)-diene in 50 ml. of methanol is heated at reflux for three hours with a solution of potassium hydroxide in 1 ml. of water. The reaction mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water to neutrality, and dried to yield 313- (5',6'-dihydro-2H-pyran-4-yloxy) 17a ethynyl-19-norandrosta-4,9(10)-dien-17B-ol which is recrystallized from methylene chloride ether.

Similarly, the other 17B-ester products of Example 24 are converted to the corresponding 17,8-ols by this procedure.

EXAMPLE 26 Repeating the procedure of Example 21 but replacing l'la-ethynyl-17fi-(5,6-dihydro 2H pyran-4'-yloxy)-19- norandrosta-4,9(10)-dien-3 -one with 17wethynyl-19-norandrosta-4,9(10)-dien-17fi-ol-3-one17a ethynyl 19- norandrosta-4,9(10)-diene-3B,17,B-diol is obtained. Then repeating the procedure of Example 1 but replacing 3- methoxy-l7ot-ethynylandrosta 3,5 dien 17B 01 with 17rx-ethynyl-19-norandrosta 4,9(10) diene 35,17fldiol and using 4 ml. instead of 2 ml. of 4'-methoxy-5,6'- dihydro 2H pyran-3,8,17/3 bis(5',6 dihydro 2H- pyran-4'-yloxy)-l7u-ethynyl 19 norandrosta-4,9(10)- diene is obtained.

Repeating this sequence of procedures with other 19- norandrosta-4,9(10)-dien 17,8 ol 3 ones and 19- 22 norandrosta-4,9(10),11-trien-17/3-ol-3-ones having lower alkenyl (e.g., vinyl, propenyl), lower alkynyl, lower haloalkynyl (e.g., ethynyl, methylethynyl, chloroethynyl, or fiuoroethynyl), cyclopropenyl, and halocyclopropenyl groups at C17a and hydrogen or methyl at ClS yields the corresponding 36,17/3-bisethers, e.g., 3,8,17B-bis(5,6- dihydro-ZH-pyran 4' yloxy) 17a ethynylandrosta-4, 9(10)-diene, 35,175-bis(5,6-dihydro-2H-pyran-4-yloxy)- 17a-et hynyl-1S-methyl-19-norandrosta4,4( 10),11-triene, and the like.

The invention claimed is: 1. A 5',6'-dihydro-2H-pyran-4-yl ether selected from the group consisting of (a) 17,8-(5,6-dihydro 2H-pyran-4'-yloxy)androsta- 3,5-dienes and 17;? (5,6-dihydro-2H-pyran-4'-yloxy)-19-norandrosta-3,5 dienes having at position C3, lower alkoxy or lower cycloalkoxy; at position C17oz, lower alkenyl, lower alkynyl, lower haloalkynyl, or

wherein R and R each is hydrogen, chloro, or fluoro; at position C18, hydrogen or methyl;

(b) androst-4-enes, 19-norandrost-4-enes, androsta-4,6

dienes, or 19-norandrosta-4,6-dienes having at position C-3, keto or 1 wherein R is 5,6-dihydro-2H-pyran 4 yloxy, hydrogen, hydroxy, or conventional hydrolyzable esters thereof; at position C6 when the bond between carbons C6 and C7 is a double bond and at each of positions CGa and C- when the bond between carbons C6 and C7 is a single bond, hydrogen, methyl, chloro, or fiuoro; at position C17a, lower alkenyl, lower alkynyl, lower haloalkynyl, or

wherein R and R each is hydrogen, chloro, or fiuoro; at C17fi, hydroxy, conventional hydrolyzable esters thereof, or 5,6 dihydro-2H-pyran-4- yloxy, and at least one of said C-3 and (3-175 positions having said 5',6' dihydro-2H-pyran-4-yloxy group; and at position C18, hydrogen or methyl; (0) 19-norandrost-5(10)-enes having at position C3,

keto or wherein R is hydrogen, hydroxy, conventional hydrolyzable esters thereof, or 5,6-dihydro-2H-pyran- 4'-yloxy; at position Cl7ot, ethynyl, methylethynyl, chloroethynyl, or fiuoroethynyl; at position C-17 8, hydroxy, conventional hydrolyzable esters thereof, or 5,6-dihydro-2H-pyran-4'-yloxy, and at least one of said C3 and C17,8 positions having said 5',6- dihydro-ZH pyran-4'-yloxy group; and at position C18, hydrogen or methyl; (d) 19-norandrosta-4,9(10)-dienes or 19-norandrosta- 4,9(10),11-trienes having at position C3, keto or R50 I. H wherein R is 5,6-dihydro-2H-pyran-4-yloxy, hydrogen, hydroxy, or conventional hydrolyzable esters thereof; at position C17a, lower alkenyl, lower alkynyl, lower haloalkynyl, or

wherein R and R each is hydrogen, chloro, or fluoro; at position C-17fl, hydroxy, conventional hydrolyzable esters thereof, or 5',6' dihydro-2H- pyran-4'-yloxy and at least one of said C-3 and C-17fi positions having said 5',6-dihydro-2H-pyran- 4'-yloxy and at position C-18, hydrogen or methyl; and

(e) 35 (5,6' dihydro 2H pyran 4 yloxy) pregn-4-en-20-ones and 3,8-(5,6'-dihydro-2H-pyran- 4'-yloxy)-19-norpregn-4-en-20-ones having at position C1,2, hydrogens or wherein each of R and R is hydrogen, chloro, or fluoro; at position C-6, hydrogen, methyl, fluoro, or chloro; at position C-9oc, hydrogen, chloro, or fiuoro, except with 35 (5',6'-dihydro-2H-pyran-4'- yloxy)-19-norpregn-4-en-20-ones wherein hydrogen is at C-9a when hydrogen is at C-lLB; at position C-1 1, keto or wherein R is hydrogen, chloro, or hydroxyl; at position -16, methylene or wherein R and R each is hydrogen or methyl; at position C-17a, hydrogen, hydroxyl, hydrolyzable esters thereof or, taken together with C-16oz,

wherein each of R and R is hydrogen, alkyl, or aryl, the latter two having up to eight carbons; at position C-21, hydrogen or fiuoro; and between the carbons at positions C- and 0-6, a single bond, double bond, or single bond together with the methylene group 1 Rsz wherein R and R each is hydrogen, fiuoro, or

chloro. 2. The steroid ether of claim 1 wherein the ether is a member selected from the group consisting of 17(3-(5',

6'-dihydro 2H pyran 4'-yloxy)androsta-3,5-dienes I and 17,8 (5,6 dihydro-2H-pyran-4-yloxy)-19-norandrosta-3,5-dienes having at position 0-3, a member selected from the group consisting of lower alkoxy and lower cycloalkoxy; at position 17oz, a member selected from the group consisting of lower alkenyl, lower alkynyl, lower haloalkynyl, and 2,2"-difiuorocyclopropenyl; and at C-18, a member selected from the group con sisting of hydrogen and methyl.

3-. The steroid ether of claim 2 wherein the ether is 3-cyclopentoxy-l7owethynyl-17fi- (5,6-dihydro-2H-pyran- 4-yloxy)-19-nonandrosta-3,S-diene.

4. The steroid ether of claim 2 wherein the ether is 3-cyclopentoxy 17oz ethynyl-1713-(5,6'-dihydro-2H-pyran-4-yloxy)-lS-methyl-19-norandrosta-3,S-diene.

5. The steroid ether of claim 2 wherein the other is 3- ethoxy 17oz ethynyl 17 3 (5,6'-dihydro-2H-pyran-4'- yloxy)-androsta-3,5-diene.

6. The steroid ether of claim 1 wherein the ether is selected from the group consisting of androst-4-enes, 19- norandrost 4 enes, androsta-4 ,6-dienes, and 19-no-randrosta-4,6-dienes having at position C-3, a member selected from the group consisting of keto and l. .11 wherein R is 5',6-dihydro-2H-pyran-4'-yloxy, hydrogen, hydroxy, or conventional hydrolyzable esters thereof; at position C6 when the bond between carbons C-6 and (3-7 is a double bond; at each of positions C-6oz and 0-65 when the bond between C-6 and C-7 is a single bond, members selected from the group consisting of hydrogen, methyl, fluoro, and chloro; at position C-17tx, a member selected from the group consisting of lower alkenyl, lower alkynyl, lower haloalkynyl, and

wherein R and R each is hydrogen, chloro, or fluoro; at C4713, a member selected from the group consisting of hydroxy, conventional hydrolyzable esters of said hydroxy, and 5,6-dihydro-2H-pyran-4-yloxy, and at least one of said C-3 and C-17/3 having said 5',6-dihydro 2H-pyran-4-yloxy; and at C-18, a member selected from the group consisting of hydrogen and methyl groups.

7. The steroid ether of claim 6 wherein the ether is 17a-ethynyl-17/3-(5,6'-dihydro 2H pyran-4'-y1oXy)-19- norandrost-4-en-3-one.

8. The steriod ether of claim 6 wherein the ether is 3fl-acetoxy a ethynyl-17p-(5',6' -dihydro-2H-pyran- 4'-y1oxy l 9-no randrost-4-ene.

9. The steroid ether of claim 6 wherein the ether is 17a-ethynyl-17p-(5,6'-dihydro 2H pyran-4'-yloxy)-18- methyl-19-norandrost-4-ene-3-one.

10. The steroid ether of claim 6 wherein the ether is 3-acetoxy-17.a-ethynyl-17;8-(5,6'-dihydro 2H pyran-4'- yloxy) -l8-methyl-19-norandrost-4-ene.

11. The steriod ether of claim 6 wherein the ether is 6u-fluoro 17a ethynyl-17,8-(5',6 dihydro-2H-pyran-4'- yloxy) -19-norandrost-4-en-3-one.

12. The steroid ether of claim 6 wherein the ether is 6a-fluoro 17a ethynyl-17/8-(5,6' dihydro-2H-pynan-4- yloxy)-18-methyl-l9-norandrost-4-en-3-one.

13. The steroid ether of claim 6 wherein the ether is 6u-methyl-17a-ethynyl-17 8-(5,6'-dihydro 2H pyran-4'- yloxy)-19-norandrosta-4,6-dien-3-one.

14. The steroid ether of claim 6 wherein the ether is 6ot-methyl-l7a-ethynyl-17 3-(5,6-dihydro 2H pyran-4'- yloxy) -l8-methyl-19-norandrosta-4,6-dien-3-one.

15. The steroid ether of claim 6 wherein the ether is 6u-methyl 17a methylethynyl 17;? (5,6'-dihydro-2H- pyran-4-yloxy androst-4-en-3-one.

16. The steroid ether of claim 6 wherein the ether is 3-(5,6-dihydro 2H pyran 4 yloxy)-17iu-ethynyl-19- norandrost-4-en-17B-ol.

17. The steroid ether of claim 6 wherein the ether is 3 (5',6 dihydro-2H-pyran-4'-yloxy)17a-ethynyl-17fiacetoxy-l9-norandrost-4-ene.

18. The steroid ether of claim 6 wherein the ether is 3,17 3 bis(5,6' dihydro-2H-pyran-4-yloxy)-17a-ethynyl-l9-norandrost-4-ene.

19. The steroid ether of claim 1 wherein the ether is a 19-norandrost-5(10)-ene having at position C-3, member selected from the group consisting of keto and like wherein R is hydrogen, hydroxy, conventional hydrolyzable esters of said hydroxy, or 5,6'-dihydro-2Hpyran-4' yloxy; at position Cl7a, a member selected from the group consisting of ethynyl, methylethynyl, chloroethynyl, and fiuoroethynyl; at position C17,8, a member selected from the group consisting of hydroxy, conventional hydrolyzable esters of said hydroxy and 5,6'-dihydro-2H- pyran-4'-yloxy, at least one of said C-3 and 0-175 having 25 said ,6'-dihydro-2H-pyran-4-yloxy group; and at position C-18, a member selected from the group consisting of hydrogen and methyl.

20. The steroid ether of claim 19 wherein the ether is 17cc ethynyl 17p-(5,6'-dihydro-2H-pyran-4-yloxy)-19- norandrost-S -en-3-one.

21. The steroid ether of claim 19 wherein the ether is 170: ethynyl-17(3-(5,6'-dihydro-2H-pyran-4'-yloxy)-18- methyl-19-norandrost-5 10) -en-3-one.

22. The steroid ether of claim 1 wherein the ether is a member selected from the group consisting of 19-norandrosta-4,9(10)-dienes and l9-norandrosta-4,9(l0),11- trienes having at position C-3, a member selected from the group consisting of keto and Ran wherein R is 5,6'-dihydro-2H-pyran-4'-yloxy, hydrogen, hydroxy, or conventional hydrolyzable esters thereof; at position C-17a, a member selected from the group consisting of lower alkenyl, lower alkynyl, lower haloalkynyl. and

C=CH wherein R and R each is hydrogen, chloro, or fluoro; at position C17/3, a member selected from the group consisting of hydroxy, conventional hydrolyzable esters thereof, and 5',6' dihydro 2H pyran 4 yloxy and at least one of said C-3 and C-17B positions having said 5,6 dihydro 2H pyran 4' yloxy and at position C-18, a member selected from the group consisting of hydrogen and methyl.

23. The steroid ether of claim 22 wherein the ether is 170: chloroethynyl 175 (5',6' dihydro 2H pyran- 4-yloxy)-19-norandrosta-4,9(10)-dien-3-one.

24. The steroid ether of claim 22 wherein the ether is 17m ethynyl 17B (5,6 dihydro 2H pyran 4- yloxy)-19-norandrosta-4,9(10),11-trien-3-one.

25. The steroid ether of claim 22 wherein the ether is 17a ethynyl 17f! (5,6 dihydro 2H pyran 4- yloxy)-18-methyl-l9-norandrosta-4,9(10),l1-trien-3-one.

26, The steroid ether of claim 1 wherein the ether is a member selected from the group consisting of 3 3-(5',6- dihydro 2H pyran 4 yloxy)pregn 4 en 20 ones and 3,8 (5,6' dihydro 2H pyran 2' yloXy) l9- norpregn-4-en-20-ones having at position C1,2, a member selected from the group consisting of hydrogens and the methylene group aa E ae wherein each of R and R is selected from the group consisting of hydrogen, chloro, and fluoro; having at position C-6, a member selected from the group consisting of hydrogen, methyl, fluoro, or chloro; at position C-9a, a member selected from the group consisting of hydrogen, chloro, and fluoro, except with 3f3-(5,6'-dihydro-2Hpyran 4 yloxy) 19 norpregn 4 en 20 ones wherein hydrogen is at 0-90: when hydrogen is at C-1 1,8; at position Cl1, a member selected from the group consisting of keto and wherein R is hydrogen, chloro, or hydroxyl; at position C-16, a member selected from the group consisting of methylene and wherein each of R and R is hydrogen or methyl; at position C-17a, a member selected from the group consisting of hydrogen, hydroxyl, and conventional hydrolyz- 26 able esters thereof, and taken together with C-16u, a group having the formula wherein R and R each is selected from the group consisting of hydrogen, alkyl, and aryl, the latter two groups having up to eight carbons; at position C21, a member selected from the group consisting of hydrogen and fluoro; and at position C5,6, a member selected from the group consisting of a double bond, a single bond, and a single bond in combination with a methylene group having the formula wherein R and R each is selected from the group consisting of hydrogen, chloro, and fluoro.

27. The steroid ether of claim 26 wherein the ether is 313 (5',6 dihydro 2H pyran 4 yloxy) 6 chlorol7u-acetoxypregna-4,6-dien-20-one.

28. The steroid ether of claim 26 wherein the ether is 35 (5',6 dihydro 2H pyran 4 yloxy) 6 chloro- 17ot-acetoxy-19-norpregna-4,6-dien-20-one.

29. The steroid ether of claim 26 wherein the ether is 104,20 methylene 35 (5,6' dihydro 2H pyran 4- yloxy)-6-chloro-l7a-acetoxypregna-4,6-dien-20=one.

30. The steroid ether of claim 26 wherein the ether is 3B-(5,6'-dihydro-2H-pyran-4 yloxy) 6 methyl 17aacetoxypregna-4,6-dien-ZO-one.

31. The steroid ether of claim 26 wherein the ether is 3;3-(5',6'-dihydro-2H-pyran-4'-yloxy)-6-methyl-17a acetoxy-19-norpregna-4,6-dien-20-one.

32. The steroid ether of claim 26 wherein the ether is 3fl-(5,6-dihydro-2H-pyran-4'-yloxy)-6-chloro-16 methylene-l7a-acetoxypregna-4,6-dien-20-one.

33. The steroid ether of claim 26 wherein the ether is 3;8-(5',6-dihydro-2H-pyran-4'-yloxy)-6-chloro-16 methylene-1 7u-acetoxypregna-4,6-dien-2 O-one.

34. The steroid ether of claim 26 wherein the ether is 3;8(5,6-dihydro-2H-pyran-4' yloxy) 6a methyl l6- methylene-l7a-acetoxypregn-4-en. 20-one.

35. The steroid ether of claim 26 wherein the ether is 3;3-(5',6'-dihydro-2H-pyran-4' yloxy) 60c fluoro 16amethylpregn-4-en-20-one.

36. The steroid ether of claim 26 wherein the ether is 3fl-(5',6'-dihydro-2H-pyran-4' yloxy) 6a fluoro 16flmethylpregn-4-en-20-one.

37. The steroid ether of claim 26 wherein the ether is 3B-S,6-dihydro-2H-pyran-4' yloxy) :,17oc methylphenylmethylenedioxypregn-4-en-20-one.

38. The steroid ether of claim 26 wherein the ether is 3/3-(5',6-dihydro-2H-pyran-4-yloxy)-6,8 fluoro 6a,7adifluoromethylene-17a-acetoxypregn-4-en-20-one.

39. The steroid ether of claim 26 wherein the ether is 35-(5',6-dihydro-2H-pyran-4'-yloxy)-6a,16a dimethylpregn-4-en-20-one.

40. The steroid ether of claim 26 wherein the ether is 313-(5',6'-dihydro-2H-pyran-4-yloxy)pregn-4 en 11,20- dione.

41. The steroid ether of claim 26 wherein the ether is 3,8-(5,6'-dihydro-2H-pyran-4-yloxy) 6,9a,11fi trichloro-l 7a-acetoxypregna-4,6-dien-20-one.

42. The steroid ether of claim 26 wherein the ether is 3 8-(5',6'-dihydro-2H-pyran-4-yloxy)-6-chloro 9a fluoro-17a-acetoxypregna-4, 6-dien-1 1 3-ol-20-one.

43. The steroid ether of claim 26 wherein the ether is 3fi-(5',6'-dihydro-2H-pyran-4-yloxy)-6-chloro-l7ut caproyloxypregna-4,6-dien-20-one.

44. The steroid ether of claim 26 wherein the ether is 27 28 3B-(5,6'-dihydro-2H-pyran-4'-yloxy) 6a methylpregn- 3,376,291 4/ 1968 Fried 260-23955 4-en-11,20-dione. 3,377,342 4/1968 Fried 260-239.55

References Cited UNITED STATES PATENTS 3,294,786 12/1966 Cross et a1. 260-23955 5 US. Cl. X.R.

3,313,808 4/1967 De Ruggieri et a1. 260239.55 3,332,941 7/1967 Shimizv et a1. 260-23955 2604674 3975 999 HENRY A. FRENCH, Primary Examiner 

